The process begins with a new idea directed at chemically modifying a disease process. Often the idea relates to developing a drug that will react with a new molecular target within the human body. The idea is usually generated from a thorough knowledge and understanding of disease processes and a continuing involvement with research in the specific therapeutic area of interest.

The target molecule, usually a protein, is isolated or sequestered by biological techniques. Tests are devised that can detect interactions of drug molecules with the target. Tens of thousands of potential drug substances, obtained from massive compound libraries, are then tested against the target in a process called high throughput screening (HTS). Robotics is often used to accomplish this task. HTS yields "hits" - compounds that seem to possess the ability to react with the target molecule.

Hits are then studied in detail to determine their exact chemical structure, physical properties, and biological characteristics. Hits that seem suitable from a physical, chemical, and biologic perspective may be termed "leads". A lead compound is one that will be modified to optimize its properties to one that will be the best suited to develop into a medicine - a drug "candidate".

The process of modifying a lead compound to obtain one or more drug candidates is called "lead optimization". It uses a technique called combinatorial chemistry to produce a large number of variants of the lead. The variants are again put through high throughput screening to identify substances with the best target activity profile. Each of the best compounds is studied in detail, and one, two, or perhaps three are chosen for further investigation as drug candidates.

The announcement of a drug candidate is a major milestone in the process of drug discovery and development. It marks the end of the discovery phase and the beginning of early development. The announcement is preceded by a patent search, to ensure that the patent on the candidate drug is not already taken by a rival research group, and by patenting all relevant aspects of the discovery.

Early development involves laboratory and animal studies. Small animals such as albino rats and mice are the most frequently used to ensure that the investigational product is safe for use in humans. The use of animals has diminished over the years as new bench-based techniques have become available. However, animal testing can be eliminated only for a minority of non-clinical studies and animal toxicology tests are still considered essential to drug development, and are required by government regulators before they will allow human testing. A large proportion of candidate compounds fail animal testing, leading to attrition in the pipeline. Sometimes development efforts have to be abandoned and discovery work re-initiated because all concurrent candidates failed non-clinical testing.

Candidates that prove successful in non-clinical testing are prepared for human testing. A drug formulation such as tablets, capsules, or injection, is produced and tested, and an application, known as the Investigational New Drug (IND) application is filed for regulatory approval in anticipation of permission to conduct human studies.

All potentially unsafe molecules are identified early in laboratory and animal studies so that only those molecules that are relatively safe and effective reach the stage of clinical testing. Government regulators thoroughly scrutinize the results of non-clinical testing and approve, for human testing, only those candidates for which experts feel that the potential benefits in patients will be greater than any potential risk of side-effects.

Human testing begins with Phase 1 studies in a small number of healthy volunteers who are given very small doses of the test compounds in specialized Phase 1 laboratories, in the presence of experienced doctors who have expertise in first-in-man studies. Volunteers are told about the study and all its risks. They are paid a participation fee if they decide to participate. The dose of the test compound is slowly increased over a period of several days till the frequency of minor side-effects reaches the upper end of the acceptable range, or the full dose is reached. The nature of any side effects, and the drug concentration in the body are documented. The investigational compound enters Phase 2 studies only if the potential benefits to patients continue to outweigh the risk of side effects in the opinion of government regulators and independent experts.

Phase 2 studies are conducted in a few hundred volunteer patients suffering from the disease for which the investigational compound is being developed. Patients are explained about the study and the investigational medicine, including potential benefits and all potential side effects. Those who wish to participate in the study are enrolled. Patients receive free treatment, and all blood, urine, and other diagnostic tests are paid for by the sponsor company. However, unlike volunteer subjects in Phase 1 studies, patients are usually not paid for participation in the study. The informed consent document and patient recruitment procedures are reviewed by government regulators and the Ethics Committee of the hospital in advance. Patients are free to withdraw consent at any time during the study. Phase 2 studies help in confirming that the medicine works and in determining the exact dose at which it works best. The new medicine is compared with dummy tablets, usually given on top of standard medicines for the disease so that patients are not harmed even if the experimental treatment does not work.

Many investigational drugs do not work well in these studies. Some are shown to have side effects that occur in more patients than is the case with the older medicines. In many cases the overall cost of using the new medicine works out to be too high when compared to the benefits, and therefore may not sell in preference to older, cheaper drugs. Many investigational compounds are dropped from further development for one or the other of these reasons.

Those drugs that are shown to work the best in Phase 2 studies, have the least side effects, and are expected to be the most economically viable, are mass tested in thousands of patients. This phase of drug development is called Phase 3 or full development. The investigational drug is given to many different types of patients - children and the elderly, those with different grades of severity of the disease, those taking other medicines for other diseases, those that need to take the medicine for a long time, and so on. The Phase 3 program is the most expensive part of clinical development. Studies are conducted across multiple patient recruitment sites simultaneously in many countries across continents. All the time, the new medicine is compared with older drugs to confirm that it indeed works better than currently available therapies. The drug may have to be dropped from further development if it is shown that it is only as good as cheaper, older drugs. The sponsor company will want to have such information as early in the development program as possible, so that development can be halted before too much money has been spent.

In the end, only 1 of 10 drug candidates that enter clinical testing at Phase 1 are found to be good enough to justify the high price tag that must be put on the medicine to meet the cost of development. Government regulators review the results of all the studies in great detail and sometimes visit the study sites and cross-question the investigators and sponsor staff. Only when the regulator is fully satisfied with the quality and extent of data is marketing permission given. The investigational drug is then "launched", and becomes a medicine available at the chemist shop or pharmacy.

Even after regulators have allowed the medicine for general use, a strict vigil is maintained. Doctors are required to report any unexpected side effect or suspected health risk with the new medicine as soon as possible to the regulators and the pharmaceutical company concerned. When millions of people start taking a new medicine, new side effects or health risks sometimes come to light. The frequency and extent of these is closely monitored by regulators. Sometimes, warnings and precautions must be added to the product label, and rarely, a drug may have to be withdrawn from the market.

New medicines are very expensive in the early years of sales to pay for the cost of drug development, publicize the benefits of the new therapeutic option, and provide returns to shareholders of the company. Eight to 10 years after launch the patent period expires and the drug is thrown open for other companies to manufacture and sell at low price. Patients are often not able to afford new medicines and, in most countries, the government pays for them and provides them free or at low cost to patients. Health insurance schemes offer to pay the price if the patient holds an appropriate health insurance policy. While government and pharmaceutical companies are doing their best to minimize the costs involved in drug development, the high price of innovative new medicines worldwide remains an unavoidable necessity without which there would be no new medicines. It the price we pay for medical breakthroughs in the early years of their advent so that millions of patients can enjoy their benefits in later years and live longer and healthier lives.

Clinical drug development in humans takes place in a series of phases. Phase 1 studies are the first time a new drug compound is tested in human subjects who are generally normal, healthy volunteers. These studies, often referred to as clinical pharmacology studies, are designed to determine tolerance/safety, pharmacokinetic and pharmacodynamic properties, including occasionally early indications of efficacy. The preferred route of administration and a safe dosage range are other parameters tested during this process. A phase 1 trial generally takes from 6 months to a year, and includes fewer than 100 healthy volunteers. Oncology drugs are an exception. Due to their potential for toxicity, such drugs are tested in cancer patients rather than healthy volunteers.

During this early phase exploratory work is begun to determine whether valid quality-of-life (QOL) measures are available for diseases that may be targeted for the new drug compound. If QOL measures are not available instrument development may begin.(e.g., for Viagra in erectile dysfunction, Pfizer scientists developed the International Index of Erectile Function (IIEF) questionnaire which is now used as a standard for assessing quality-of-life in trials of drugs for erectile dysfunction).

Bio-equivalence trials are done when a branded generic is sought to be marketed within 4 years of introduction of the first (often patented) brand. The imitator's pharmacokinetic profile (Tmax, Cmax, AUC) has to exactly match/superimpose that of the original drug.

Nowadays clinical trials are structured to assess not just safety and efficacy but also quality-of-life (outcomes research) and cost-effectiveness (pharmacoeconomics). Pharmacogenomics, i.e., the study of the way drugs interact with the genome or genetic make-up of an individual is another tool which is being used to selectively tailor a drug/dose to an individual. It helps in the selection of trial patients in whom the drug is predicted to have optimum efficacy and safety. Approximately one third of candidates fail during phase 1 testing due to poor toleration/absorption.

Phase 2 clinical trials are designed to provide additional safety data but the primary purpose is to determine the drug's dosage range and clinical effectiveness in its targeted population. Here, patients with the disease under investigation are studied. Typically these trials are placebo-controlled, i.e., one group is administered a placebo (inert compound which is pharmacologically inactive and is formulated to simulate the test drug in physical appearance) while the other group of patients is given the test drug.

The investigators who conduct phase 2 trials are usually experts in the disease being studied and /or in the evaluation of the drug's effects on the disease process.

Phase 2 trials generally involve between 100 and 500 subjects who have the disease/condition for which the drug is being developed.

Phase 2 studies also may determine the minimum dose of the drug that is effective, and / or the upper dose that is sufficiently effective without undue toxicity.

Sometimes reference is made to phase 2a & phase 2b studies. Phase 2a studies are pilot clinical trials designed primarily to evaluate safety in selected populations of patients. Objectives may focus on dose response, type of patient, frequency of dosing, or other characteristics related to the drug's safety. Phase 2b studies are well-controlled clinical trials designed to evaluate both efficacy and safety in patients with a primary objective of determining a dose range to be studied in phase 3.

Additionally, phase 2 studies may include pilot testing of QOL instruments to assess validity, variability and sensitivity to change. Validation is the action of proving that any process, procedure, equipment, material, activity, or system actually leads to the expected results.

Phase 3 clinical trials are well-controlled comparative studies designed to assess the safety and effectiveness of the drug in conditions approximating those in which the drug would be used if approved for marketing. They generally involve thousands of patients with a targeted disease and are frequently multi-centric. Data from these trials are pivotal for registration. A randomized, placebo and/or active controlled, double blind clinical trial is considered the gold standard to evaluate the drug's safety and efficacy. However, it is possible that some adverse events may be missed even at this juncture, only to surface after the drug has been marketed, e.g., temafloxacin was withdrawn by the U.S. F.D.A. 6 months after it was launched. It is often said that the efficacy of a drug is measured in the controlled environment (strict inclusion and exclusion criteria, close monitoring of patients) of a clinical trial while its effectiveness is known only post-registration when it is used in a much larger patient population (often not strictly monitored or selected) in the unregulated atmosphere of general clinical practice. Efficiency is yet another term in pharmaco-economics which measures the cost-effectiveness of the product and its effect on disease outcome vis-à-vis other competitor products.

Sometimes reference is made to phase 3a and 3b trials. Phase 3a trials are conducted after the drug's efficacy is demonstrated but before regulatory submission of the New Drug Application (NDA). These trials are conducted in special patient populations, e.g., studies in children and in patients of renal dysfunction. Phase 3a data may also include assessments of patient function, health-related QOL, and/or health care utilization which may assist with formulary and drug reimbursement decisions. In India the concept of managed health care and disease management organizations has yet to arrive but with increasing patient awareness of health insurance, that day is not too far.

Phase 3b trials are conducted after regulatory submission of the NDA but prior to the drug's approval and launch. They may supplement or complete earlier trials. They may also collect outcomes research data, including "real world" conditions in which the drug's clinical, QOL, and economic impacts are assessed.